STANDARD OPERATING PROCEDURE FOR CLEANING VALIDATION PROGRAM

1.0 OBJECTIVE

1.1 To establish and explain the procedure to be followed for the Validation of Standard Cleaning Procedures (SOP) s, in order to

1.1.1 Assure that fitness of the equipment is adequately protected for every product.

1.1.2 Demonstrate that no cross contamination will be observed on shared equipment between drug product to be cleaned and Drug product to be manufactured.

1.1.3 Demonstrate and validate that current Standard Cleaning Procedures can consistently clean the equipment to a pre - determined level of cleanliness.

1.1.4 Establish the length of time between the end of cleaning process and the use of the equipment, as cleaned equipment hold time.

2.0 SCOPE

2.1 This procedure is applicable for the validation of standard cleaning procedures, at …………..

3.0 RESPONSIBILITY

3.1 Executive of the concerned department shall initiate the SOPs and Executive-QA, in co-ordination with the Executive of the Production department shall prepare protocol for Cleaning Validation studies.

3.2 Executive-Quality control to develop analytical methods for estimation of residue of active ingredient, cleaning agents and validate the methods.

3.3 Executive - QC, to sample and analyze as per cleaning validation protocol.

3.4 Heads of user department, Quality Control and Quality Assurance or their designees to approve and certify Cleaning Validation Protocol for commercial and Exhibit batches.

3.5 Head QC and QA or their designees to approve and certify Cleaning Validation Protocol for Process Evaluation batches.

3.6 Head-QA shall ensure compliance of the procedure.

4.0 ACCOUNTABILITY

4.1 Head-QA/his designee

5.0 PROCEDURE

5.1 The Cleaning validation program is designed to demonstrate the effectiveness of SOP to remove residues of drug active substances, cleaning agents and microbial attributes.

5.2 After the process equipment is used for the manufacture of a product, it shall be cleaned as mentioned in respective SOP.

5.3 All the SOPs of process equipments used to manufacture more than one product shall be validated, for each product.

5.4 If the product contains multi active drug substances, the active substance least soluble in potable water and /or highly toxic is tested, unless the method validation data provides for testing of all active drugs in the combination.

5.5 Before initiating any cleaning validation, a cleaning validation protocol shall be prepared by Validation coordinator and submitted for approval to the concerned Head of the Department (HOD) Head - QC and Head-QA or their designee for commercial and Exhibit batches.

5.6 In case of Process Evaluation batches, Cleaning Validation Protocol shall be approved by Head QC and QA or their designees.

5.6.1 The cleaning validation protocol in general, shall contain the following:

5.6.1.1 Objective: Describe the objective and scope of the validation

5.6.1.2 Procedure

5.6.1.2.1 Describes the activities comprising the cleaning validation and personnel responsible for carrying out the activities.

5.6.1.2.2 Provides procedure for Preparation of Swabs and swabbing pattern.

5.6.1.2.3 Calculates and provides surface area of the equipment in common along with sampling locations, swab numbers and type of sample (Residue of drug active, Cleaning agent, Microbial)

5.6.1.3 Acceptance Criteria: Specifies the acceptance limits for the active drug substance, the cleaning agent and microbial attributes, if any.

5.6.1.4 Annexure: The protocol contains the summary of analytical results for Drug active, cleaning agent and microbiological attributes as Annexure. A copy of the analysis report given by QC laboratory shall also be enclosed to the protocol.

5.7 Swabbing shall be carried out for Microbial, Chemical and Detergent sequentially.

5.8 The approving authorities shall certify each Cleaning Validation Protocol after its satisfactory execution.

5.9 Cleaning Validation shall be performed on a minimum of three (3) consecutive production size batches. Cleaning validation with respect to Exhibit and Process Evaluation scale batches shall be carried out for evaluation purpose only.

5.10 If results for any drug active, cleaning agent and/or Microbial attributes are failing, an investigation shall be carried out and corrective action shall be taken up.

5.10.1 If acceptance criteria are not met and / or cleaning found not satisfactory, during visual inspection, the following steps shall be taken for remedial action.

5.10.1.1 Executive of concerned department shall raise an Incident Report and investigate the execution of the SOP of that particular process equipment. If found to be incorrect and deficient during investigation, clean the equipment again as per that SOP, Sample again and analyze as per the cleaning validation protocol.

5.10.1.2 If execution of SOP is found proper, revise the SOP to ensure proper cleaning of locations/parts which are found to be not satisfactorily cleaned during visual inspection or analysis of the swab samples.

5.11 Cleaning Validation Acceptance Criteria:

5.11.1 ECL (Exposure Control Level) calculation for drug active: For each drug active and ECL shall be calculated using three different methods:

A. Visually Clean Criterion

B. Dose Criterion (0.001)

C. PPM Criterion (10 ppm)

A. Visually Clean Criterion

The visually clean criteria are a fixed criterion and it shall be at 100g/swab. (Swab area 25 sq.cm)

B. Dose Criterion:

X = 0.001 x d x B x 1/D x 1/A x F x U

Where X = the residue of the drug active in mg/ Sq.cm

0.001=Safety Factor

d = Dose in lowest label strength of the product to be cleaned.

B = Minimum Batch size of the all strengths for product to be manufactured.

A = Cumulative surface area of the equipment in common to the product to be cleaned and product to be manufactured, in Sq. cm.

D = Maximum dosage units taken per day of the product to be manufactured.

F = Recovery factor (Specific to each product, shall be established by QC-Executive)

U = 25 Sq.cm/swab

Note:

If 25 Sq.cm is not available for swabbing for particular equipment, maximum available area shall be taken for calculation.

C. PPM Criterion (10 ppm)

For each drug active an ECL value shall be calculated in mg/sq.cm using the formula

X = R x S x U x F

A

X = The residue of the drug active in mg/sq.cm.

R = 10 mg active ingredient in host per kg of product to be manufactured.

S = Number of kgs per batch of final mixture of product to be manufactured.

A = Cumulative surface area of the equipment in common to the product to be cleaned

and product to be manufactured, in sq./cm

U = 25 Sq.cm/swab

F = Recovery factor (Specific to each product, shall be established by QC- Executive)

Note: If 25 Sq.cm is not available for swabbing for particular equipment, maximum

available area shall be taken for calculation.

Calculate the residue in swabbing solvent, in ppm,( X in ppm) by using the following formula

X in ppm = X in mg/Sq. cm x 1/V x 1000

V = Volume of solvent used for Extraction of Swabbed contents.

5.11.2 The value obtained for X in ppm is the maximum amount of residue of drug active permitted in any swab sample.

5.11.3 Follow the below steps before performing the ECL drug active calculations:

5.11.3.1 Prepare a matrix with all possible combinations of commercialized products which share equipment in common with the product under study by listing out the commercialized products, batch size, maximum dosage units taken per day, and equipment surface area.

5.11.3.2 For Exibit/PE/Labscale batches, calculate the ECL value only with respect to subsequent batch (Exhibit/Validation/Commercial batch).

5.11.3.3 Make the calculations in accordance with the three different methods mentioned and compare the results obtained.

5.11.4 The minimum value obtained from the above three criteria shall be taken as ECL.

5.11.5 The results obtained after ECL calculations shall be reported in whole numbers.

5.11.6 Calculate an ECL for cleaning agent (Detergent) in µg/Sq. cm using the Following

formula: (Wherever LD50 value is available).

Q x R x T x B

Y = S x D x A

5.11.6.1 If LD50 value is not available a maximum of 5 ppm/swab is allowed unless otherwise specified in the individual cleaning validation protocol.

Q = LD 50 of cleaning agent (1000g/kg) x 50 kg of body weight of a human (small adult).R = % of active ingredient in total dose of cleaning agent.

S= Safe daily exposure factor = 5 x 106 (constant)

T= 1 x 106 µg/g (conversion factor)

D = Maximum number of dosage units taken per day of product to be manufactured.

B = Minimum batch size (or smallest batch size)

A = Total equipment surface area used in process.

5.11.7 Follow the below steps before performing the ECL for cleaning agent calculations:

5.11.7.1 Using the product matrix procedural description, calculate the cleaning agent ECL in accordance to the formula above. List manufactured product, maximum dosing units/day, batch size (units), equipment train surface area, LD50 and percent of active ingredient of cleaning agent as in Material Safety Data Sheets (MSDS)

5.11.7.2 Compare results of above calculations for the cleaning agent under study with each product strength evaluated. The lowest calculated permissible residue per square cm obtained among all strengths of products evaluated with the cleaning agent.

5.11.8 Alert Limit: For each product an alert limit for Active Drug substance shall be established during cleaning Validation. The alert limit shall be 60% of the calculated limit.

5.11.9 When ever the cleaning validation results are differing significantly from the regularly observed results, for the drug active, the same shall be investigated.

5.11.10 The ECL values for drug active and detergent shall be referred to a review committee comprising of Heads of QC and QA. The limits shall be reviewed for their acceptance by considering the toxicity, sensitivity levels in all the possible subjects of different age groups.

5.12 In case the calculated ECL values are not acceptable, the committee shall recommend the alternative ECL values and it shall become effective.

5.13 Limits for microbial load:

Total Aerobic Microbial Count (TAMC) - NMT 100 CFU/25sq.cm

Total Combined Yeasts and Moulds (TCMY) - NMT 100 CFU/25sq.cm

5.14 Revalidation of Cleaning Procedures:

5.14.1 A Revalidation of the cleaning procedure is required if any of the following occur and revalidation of SOPs shall be performed on a minimum of three (3) Production batches.

5.14.2 Modification of MOC/surface area of Product contact parts of the equipment, or any modification to the equipment.

5.14.3 Change in cleaning agents.

5.14.4 Change in SOP

5.14.5 Change in Formula of the Product.

5.14.6 Major non - traceable contamination occurrence.

5.15 Periodic Monitoring Program:

5.15.1 Monitor the validation status of cleaning procedures once in a year, unless otherwise specified in the individual cleaning validation protocol of the product.

5.16 "UNDER CLEANING VALIDATION - DO NOT USE" label (Refer annexure-1) shall be kept after collecting the swabs.

5.17 Unless the interim report/analysis report is released by Quality Control to Quality Assurance department for chemical and detergent swabs results, clearance for the equipment usage shall not be given by Quality Assurance for the next product.

5.18 In case of microbial analysis results of swab samples, no need to wait for the release of results.

5.19 Numbering of Validation Protocol:

5.19.1 Each validation protocol shall have a unique number.

5.19.2 The number consists of eight characters.

5.19.3 The first two characters denote VC, which means it, is cleaning validation protocol.

5.19.4 The third and fourth characters shall be follows: PD – Production.

5.19.5 The fifth character shall be a dash.

5.19.6 The sixth, seventh and eighth characters indicates the serial number.

Eg: The first protocol belonging to PD shall be VCPD-001.

5.19.7 Details shall be recorded in the register.

6.0 ABBREVIATIONS

6.1 QA - Quality Assurance

6.2 SOP - Standard Operating Procedure

6.3 ECL - Exposure control level

6.4 QC - Quality control

6.5 PPM - Parts per million

7.0 REFERENCES

7.1 Nil

8.0 ANNEXURES

8.1 Annexure: 1 - Specimen Label for “Under Cleaning Validation – Do Not use”.

8.2 Annexure: 2 - Format for “Register for Numbering Cleaning Validation Protocols”





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